This Program Project presents, brings together, and links five projects designed to investigate the biological effects of alpha particles with LETs simulating those emitted by the daughter products of radon. The individual projects each address this central theme from different points of view. The earliest observable biological effect of radiation in individual cells is the production of chromosome aberrations, and their production by alpha particles will be studied in detail. The special feature of this project is the attempt to quantitate the effect of precisely known numbers of alpha particles traversing single cells. This is particularly important, as it is likely that most cells at risk will be traversed by no more than one alpha particle. Since the hazard of radon in the human involves the stochastic late effects of carcinogenesis, the experimental studies focus directly on oncogenic transformation and on mutations or DNA modulations, which may be early steps involved in the carcinogenic process. A variety of cellular and molecular studies are proposed in this area. Assays for oncogenic transformation represent a powerful tool and will be used for pragmatic studies involving the possible supra-additive interaction of alpha particles with asbestos, tobacco-smoke condensate, and a variety of chemicals, as well as the study of modulating influences, such as hormones and retinoids. Mechanistic studies will be designed to identify and characterize the molecular changes that lead to the induction of malignancy. The alpha particles emitted by the radon daughters cover a range of energies, and by the time they reach the critical cells in the lung, they have LET values from about 90 to 250 keV/(mu)m. Alpha particles with this range of LET values will be generated at the Radiological Research Accelerator Facility.